Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR

Claudia L Kleinman¹, Noha Gerges², Simon Papillon-Cavanagh³, Patrick Sin-Chan⁴, Albena Pramatarova³, Dong-Anh Khuong Quang⁵, Véronique Adoue³, Stephan Busche³, Maxime Caron³, Haig Djambazian³, Amandine Bemmo³, Adam M Fontebasso⁶, Tara Spence⁴, Jeremy Schwartzentruber³, Steffen Albrecht⁷, Peter Hauser⁸, Miklos Garami⁸, Almos Klekner⁹, Laszlo Bognar⁹, Jose-Luis Montes¹⁰, Alfredo Staffa³, Alexandre Montpetit³, Pierre Berube³, Magdalena Zakrzewska¹¹, Krzysztof Zakrzewski¹², Pawel P Liberski¹¹, Zhifeng Dong¹³, Peter M Siegel¹³, Thomas Duchaine¹⁴, Christian Perotti¹⁵, Adam Fleming¹⁶, Damien Faury¹⁶, Marc Remke¹⁷, Marco Gallo¹⁷, Peter Dirks¹⁷, Michael D Taylor¹⁷, Robert Sladek¹⁸, Tomi Pastinen³, Jennifer A Chan¹⁵, Annie Huang¹⁹, Jacek Majewski¹, Nada Jabado²⁰

Affiliations

¹ 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3].
² 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
³ McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
⁴ Division of Hematology-Oncology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
⁶ Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
⁷ Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada.
⁸ Second Department of Paediatrics, Semmelweis University, Budapest, Hungary.
⁹ Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
¹⁰ Division of Neurosurgery, Department of Surgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
¹¹ Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
¹² Department of Neurosurgery, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
¹³ Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
¹⁴ Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
¹⁵ Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁶ Division of Pediatric Hematology-Oncology, Department of Pediatrics, McGill University and the McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
¹⁷ Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁸ 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
¹⁹ 1] Division of Hematology-Oncology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Program in Cell Biology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. [3].
²⁰ 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. [3].

PMID: 24316981
DOI: 10.1038/ng.2849

Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR

Claudia L Kleinman et al. Nat Genet. 2014 Jan.

. 2014 Jan;46(1):39-44.

doi: 10.1038/ng.2849. Epub 2013 Dec 8.

Authors

Affiliations

¹ 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [3].
² 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2].
³ McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada.
⁴ Division of Hematology-Oncology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
⁶ Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
⁷ Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada.
⁸ Second Department of Paediatrics, Semmelweis University, Budapest, Hungary.
⁹ Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.
¹⁰ Division of Neurosurgery, Department of Surgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
¹¹ Department of Molecular Pathology and Neuropathology, Medical University of Lodz, Lodz, Poland.
¹² Department of Neurosurgery, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
¹³ Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.
¹⁴ Department of Biochemistry, McGill University, Montreal, Quebec, Canada.
¹⁵ Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
¹⁶ Division of Pediatric Hematology-Oncology, Department of Pediatrics, McGill University and the McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
¹⁷ Division of Neurosurgery, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁸ 1] McGill University and Génome Québec Innovation Centre, Montreal, Quebec, Canada. [2] Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
¹⁹ 1] Division of Hematology-Oncology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada. [2] Program in Cell Biology, Arthur & Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada. [3].
²⁰ 1] Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [2] Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada. [3].

PMID: 24316981
DOI: 10.1038/ng.2849

Abstract

Embryonal tumors with multilayered rosettes (ETMRs) are rare, deadly pediatric brain tumors characterized by high-level amplification of the microRNA cluster C19MC. We performed integrated genetic and epigenetic analyses of 12 ETMR samples and identified, in all cases, C19MC fusions to TTYH1 driving expression of the microRNAs. ETMR tumors, cell lines and xenografts showed a specific DNA methylation pattern distinct from those of other tumors and normal tissues. We detected extreme overexpression of a previously uncharacterized isoform of DNMT3B originating at an alternative promoter that is active only in the first weeks of neural tube development. Transcriptional and immunohistochemical analyses suggest that C19MC-dependent DNMT3B deregulation is mediated by RBL2, a known repressor of DNMT3B. Transfection with individual C19MC microRNAs resulted in DNMT3B upregulation and RBL2 downregulation in cultured cells. Our data suggest a potential oncogenic re-engagement of an early developmental program in ETMR via epigenetic alteration mediated by an embryonic, brain-specific DNMT3B isoform.

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Comment in

A developmental program drives aggressive embryonal brain tumors.
Archer TC, Pomeroy SL. Archer TC, et al. Nat Genet. 2014 Jan;46(1):2-3. doi: 10.1038/ng.2857. Nat Genet. 2014. PMID: 24370739

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Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR

Affiliations

Fusion of TTYH1 with the C19MC microRNA cluster drives expression of a brain-specific DNMT3B isoform in the embryonal brain tumor ETMR

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Medical

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